We have used brain tissue from clinically well-documented and neuropathologically confirmed cases of sporadic Parkinson's disease to establish the transcriptomic expression profile of the medial and ...lateral substantia nigra. In addition, the superior frontal cortex was analyzed in a subset of the same cases. DNA oligonucleotide microarrays were employed, which provide whole human genome coverage. A total of 570 genes were found to be differentially regulated at a high level of significance. A large number of differentially regulated expressed sequence tags were also identified. Levels of mRNA sequences encoded by genes of key interest were validated by means of quantitative real-time polymerase chain reaction (PCR). Comparing three different normalization procedures, results based on the recently published GeneChip Robust Multi Array algorithm were found to be the most accurate predictor of real-time PCR results. Several new candidate genes which map to PARK loci are reported. In addition, the DNAJ family of chaperones is discussed in the context of Parkinson's disease pathogenesis.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Helicoverpa armigera and Helicoverpa zea are major caterpillar pests of Old and New World agriculture, respectively. Both, particularly H. armigera, are extremely polyphagous, and H. armigera has ...developed resistance to many insecticides. Here we use comparative genomics, transcriptomics and resequencing to elucidate the genetic basis for their properties as pests.
We find that, prior to their divergence about 1.5 Mya, the H. armigera/H. zea lineage had accumulated up to more than 100 more members of specific detoxification and digestion gene families and more than 100 extra gustatory receptor genes, compared to other lepidopterans with narrower host ranges. The two genomes remain very similar in gene content and order, but H. armigera is more polymorphic overall, and H. zea has lost several detoxification genes, as well as about 50 gustatory receptor genes. It also lacks certain genes and alleles conferring insecticide resistance found in H. armigera. Non-synonymous sites in the expanded gene families above are rapidly diverging, both between paralogues and between orthologues in the two species. Whole genome transcriptomic analyses of H. armigera larvae show widely divergent responses to different host plants, including responses among many of the duplicated detoxification and digestion genes.
The extreme polyphagy of the two heliothines is associated with extensive amplification and neofunctionalisation of genes involved in host finding and use, coupled with versatile transcriptional responses on different hosts. H. armigera's invasion of the Americas in recent years means that hybridisation could generate populations that are both locally adapted and insecticide resistant.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The neonatal crystallizable fragment receptor (FcRn) functions as an intracellular protection receptor for immunoglobulin G (IgG). Recently, several clinical studies have reported the lowering of ...circulating monomeric IgG levels through FcRn blockade for the potential treatment of autoimmune diseases. Many autoimmune diseases, however, are derived from the effects of IgG immune complexes (ICs). We generated, characterized, and assessed the effects of SYNT001, a FcRn-blocking monoclonal antibody, in mice, nonhuman primates (NHPs), and humans. SYNT001 decreased all IgG subtypes and IgG ICs in the circulation of humans, as we show in a first-in-human phase 1, single ascending dose study. In addition, IgG IC induction of inflammatory pathways was dependent on FcRn and inhibited by SYNT001. These studies expand the role of FcRn in humans by showing that it controls not only IgG protection from catabolism but also inflammatory pathways associated with IgG ICs involved in a variety of autoimmune diseases.
We calibrated the Multiple Element Limitation (MEL) model to Alaskan arctic tundra to simulate recovery of thermal erosion features (TEFs) caused by permafrost thaw and mass wasting. TEFs could ...significantly alter regional carbon (C) and nutrient budgets because permafrost soils contain large stocks of soil organic matter (SOM) and TEFs are expected to become more frequent as the climate warms. We simulated recovery following TEF stabilization and did not address initial, short-term losses of C and nutrients during TEF formation. To capture the variability among and within TEFs, we modeled a range of post-stabilization conditions by varying the initial size of SOM stocks and nutrient supply rates.
Simulations indicate that nitrogen (N) losses after the TEF stabilizes are small, but phosphorus (P) losses continue. Vegetation biomass recovered 90% of its undisturbed C, N, and P stocks in 100 years using nutrients mineralized from SOM. Because of low litter inputs but continued decomposition, younger SOM continued to be lost for 10 years after the TEF began to recover, but recovered to about 84% of its undisturbed amount in 100 years. The older recalcitrant SOM in mineral soil continued to be lost throughout the 100-year simulation.
Simulations suggest that biomass recovery depended on the amount of SOM remaining after disturbance. Recovery was initially limited by the photosynthetic capacity of vegetation, but became co-limited by N and P once a plant canopy developed. Biomass and SOM recovery was enhanced by increasing nutrient supplies, but the magnitude, source, and controls on these supplies are poorly understood. Faster mineralization of nutrients from SOM (e.g., by warming) enhanced vegetation recovery but delayed recovery of SOM. Taken together, these results suggest that although vegetation and surface SOM on TEFs recovered quickly (25 and 100 years, respectively), the recovery of deep, mineral soil SOM took centuries and represented a major ecosystem C loss.
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BFBNIB, FZAB, GIS, IJS, INZLJ, KILJ, NLZOH, NMLJ, NUK, OILJ, PNG, SAZU, SBCE, SBMB, UL, UM, UPUK, ZRSKP
► In a large cohort study (n=852) we evaluate 74 candidate biomarkers of ageing. ► Each candidate was tested for association with 4 health-status measures. ► 10 biomarkers were significantly ...associated with two or more health-status measures. ► Inflammation/immune risk markers and telomere length did not feature among these.
Sensitive and specific biomarkers of ageing are needed to evaluate interventions to extend health span. However, there is growing evidence that information provided by candidate biomarkers may change with age itself. Little is yet known about the value of candidate biomarkers in those over 85 years, currently the fastest growing population sub-group in many countries. This study assessed a large panel of candidate biomarkers in a cohort of 85 years old by studying comparative associations with health status. Using a cross-sectional sample of 852 individuals aged 85, we performed uni- and multi-variable analyses of associations between 74 candidate biomarkers and 4 health-status measures: viz. multi-morbidity, cognitive impairment, disability and proximity to death as measured by mortality within 1.5 years. We defined as most informative any measures that were significantly associated with at least two of the health-status measures in multivariable analyses in this age group. 10 out of 74 tested candidates fulfilled this criterion, while several proposed biomarkers of ageing, notably inflammation and immune risk markers and telomere length, did not. As future data accrues on health outcomes within the cohort, it will become possible also to evaluate the predictive value of these and others of the candidate biomarkers.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Abstract The pathological basis of dementia and visual hallucinations in Parkinson's disease (PD) is not yet fully understood. To investigate this further we have conducted a clinico-pathological ...study based on 30 post-mortem PD brains. PD cases were stratified into groups according to clinical characteristics as follows: (1) cognitively intact ( n = 9); (2) cases with severe dementia and visual hallucinations ( n = 12); (3) cases with severe dementia and no visual hallucinations ( n = 4); and (4) cases with severe visual hallucinations and no dementia ( n = 5). The extent of α-synuclein (αSyn), tau and amyloid β peptide (Aβ) deposition was then examined in the CA2 sector of the hippocampus and in neocortical and subcortical areas known to subserve cognitive function. We find that dementia in PD is significantly associated with αSyn in the anterior cingulate gyrus, superior frontal gyrus, temporal cortex, entorhinal cortex, amygdaloid complex and CA2 sector of the hippocampus. Aβ in the anterior cingulate gyrus, entorhinal cortex, amygdaloid complex and nucleus basalis of Meynert is also associated with dementia as is tau in the CA2 sector of the hippocampus. αSyn burden in the amygdala is strongly related to the presence of visual hallucinations but only in those PD cases with concomitant dementia. Statistical analysis revealed that αSyn burden in the anterior cingulate gyrus could differentiate demented from non-demented PD cases with high sensitivity and specificity. We conclude that αSyn in limbic regions is related to dementia in PD as well as to visual hallucinations when there is an underlying dementia.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
Summary
Data on vitamin D status in very old adults are lacking. The aim of this study was to assess 25-hydroxyvitamin D 25(OH)D concentrations and its predictors in 775 adults aged 85 years old ...living in North-East England. Low 25(OH)D was alarmingly high during winter/spring months, but its biological significance is unknown.
Introduction
Despite recent concerns about the high prevalence of vitamin D deficiency in much of the British adult and paediatric population, there is a dearth of data on vitamin D status and its predictors in very old adults. The objective of the present study was to describe vitamin D status and its associated factors in a broadly representative sample of very old men and women aged 85 years living in the North East of England (55° N).
Methods
Serum concentrations of 25-hydroxyvitamin D 25(OH)D were analysed in 775 participants in the baseline phase of the Newcastle 85+ cohort study. Season of blood sampling, dietary, health, lifestyle and anthropometric data were collected and included as potential predictors of vitamin D status in ordinal regression models.
Results
Median serum 25(OH)D concentrations were 27, 45, 43 and 33 nmol/L during spring, summer, autumn and winter, respectively. The prevalence of vitamin D deficiency according to North American Institute of Medicine guidelines serum 25(OH)D <30 nmol/L varied significantly with season with the highest prevalence observed in spring (51 %) and the lowest prevalence observed in autumn (23 %;
P
< 0.001). Reported median (inter-quartile range) dietary intakes of vitamin D were very low at 2.9 (1.2–3.3) μg/day. In multivariate ordinal regression models, non-users of either prescribed or non-prescribed vitamin D preparations and winter and spring blood sampling were associated with lower 25(OH)D concentrations. Dietary vitamin D intake, disability score and disease count were not independently associated with vitamin D status in the cohort.
Conclusion
There is an alarming high prevalence of vitamin D deficiency (<30 nmol/L) in 85-year-olds living in North East England at all times of the year but particularly during winter and spring. Use of vitamin D containing preparations (both supplements and medications) appeared to be the strongest predictor of 25(OH)D concentrations in these very old adults.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
There is growing evidence that dysfunction of the mitochondrial respiratory chain and failure of the cellular protein degradation machinery, specifically the ubiquitin-proteasome system, play an ...important role in the pathogenesis of Parkinson's disease. We now show that the corresponding pathways of these two systems are linked at the transcriptomic level in Parkinsonian substantia nigra. We examined gene expression in medial and lateral substantia nigra (SN) as well as in frontal cortex using whole genome DNA oligonucleotide microarrays. In this study, we use a hypothesis-driven approach in analysing microarray data to describe the expression of mitochondrial and ubiquitin-proteasomal system (UPS) genes in Parkinson's disease (PD). Although a number of genes showed up-regulation, we found an overall decrease in expression affecting the majority of mitochondrial and UPS sequences. The down-regulated genes include genes that encode subunits of complex I and the Parkinson's-disease-linked UCHL1. The observed changes in expression were very similar for both medial and lateral SN and also affected the PD cerebral cortex. As revealed by "gene shaving" clustering analysis, there was a very significant correlation between the transcriptomic profiles of both systems including in control brains. Therefore, the mitochondria and the proteasome form a higher-order gene regulatory network that is severely perturbed in Parkinson's disease. Our quantitative results also suggest that Parkinson's disease is a disease of more than one cell class, i.e. that it goes beyond the catecholaminergic neuron and involves glia as well.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
The earliest cell fate decision in the mammalian embryo separates the extra-embryonic
trophoblast lineage, which forms the fetal portion of the placenta, from the
embryonic cell lineages. The body ...plan of the embryo proper is established
only later at gastrulation, when the pluripotent epiblast gives rise to the
germ layers ectoderm, mesoderm and endoderm. Here we show that the T-box gene
Eomesodermin performs essential functions in both trophoblast
development and gastrulation. Mouse embryos lacking Eomesodermin arrest
at the blastocyst stage. Mutant trophoectoderm does not differentiate into
trophoblast, indicating that Eomesodermin may be required for the development
of trophoblast stem cells. In the embryo proper, Eomesodermin
is essential for mesoderm formation. Although the specification of the
anterior-posterior axis and the initial response to mesoderm-inducing
signals is intact in mutant epiblasts, the prospective mesodermal cells are
not recruited into the primitive streak. Our results indicate that Eomesodermin
defines a conserved molecular pathway controlling the morphogenetic movements
of germ layer formation and has acquired a new function in mammals in the
differentiation of trophoblast.
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DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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